The present invention relates to a compound of oxazaborolidine type attached to a material chosen from Raney nickel, Raney cobalt and Raney iron, to its process of preparation and to the use of this compound as catalyst for the reaction of reduction of ketone to produce chiral alcohols.
Chiral alcohols are often used in the pharmaceutical industry as intermediates in the synthesis of pharmaceutical active principles. Thus, the enantioselective reduction of prochiral ketones, which results in corresponding optically active secondary alcohols, is a subject of great interest.
Generally, the process comprises a reduction stage in which a prochiral ketone is reacted with a boron-based reducing agent in the presence of a catalyst of oxazaborolidine type. The boron-based reducing agent can be the dimethyl sulfide-borane complex or the tetrahydrofuran-borane complex or else the N,N-diethylaniline-borane complex or the 1,4-thioxane-borane complex. This reaction is represented in particular in FIG. 1. According to an alternative form of this process, the oxazaborolidine is replaced by its precursor, an aminoalcohol, which is converted in situ, during the reduction, to oxazaborolidine.
The attachment of these catalysts of oxazaborolidine type or precursors to insoluble polymers has already been described, this attachment allowing the catalyst to be easily separated from the reaction medium and optionally to be reused. Various chiral aminoalcohols have thus been bonded to crosslinked polystyrenes and then converted to polystyrene-oxazaborolidines (J. Chem. Soc. Perkin Trans., 1, 345-349 (1995); Tetrahedron: Asymmetry, Vol. 6, No. 11, pp. 2755-2766 (1995), Elsevier Science Ltd; J. Chem. Soc. Perkin. Trans., 1, 2887-2893 (1984)).
The process for attaching oxazaborolidine to polymers, such as polystyrenes, is complicated to employ since it generally consists in carrying out four stages. The final stage leads to the formation of water, which it is necessary to thoroughly remove. In addition, an organic polymer generally promotes the retention and the trapping of the molecules of reactants or products; consequently, it is often necessary to carry out several extractions or washings of said polymer. Furthermore, the catalytic reaction requires a stirring capable of denaturing the polymer used.
Compounds of oxazaborolidine type have also been attached to nickel nanoparticles (Tetrahedron Letters, 40 (1999), 8375-78). The process for the preparation of these compounds, which results in the formation of NiB2, consists in reacting nickel iodide with lithium borohydride and then subsequently in mixing the suspension of NiB2 in a solvent with norephedrine. However, the separation of these compounds used as catalyst in a reaction is not always easy.
The aim of the present invention is thus to provide a novel type of catalyst which can be used in the preparation of chiral alcohols by reduction of prochiral ketones which exhibits satisfactory yields and satisfactory enantiomeric excesses.
Another aim of the present invention is to be able to make available a catalyst which readily separates from the solvent comprising the product obtained and thus to be able to reuse it without a significant decline in its performance.
These aims and others are achieved by the present invention, which relates to a compound of oxazaborolidine type attached to a material selected from Raney nickel, cobalt and iron.
Said materials are accessible to a person skilled in the art. They are generally found in the form of Raney grains with a diameter of 1000 to 10000 xc3x85 which correspond to agglomerates of crystallites with a diameter of 70 to 80 xc3x85.
Preferably, the material is Raney nickel.
More specifically, this compound of oxazaborolidine type exhibits the following formula (I): Ni5B1xe2x88x92x (oxaza)x, where x is a real number between 0 and 0.5 exclusive and oxaza exhibits the following formula: 
in which the nitrogen and oxygen atoms are connected, on the one hand, via a boron atom and, on the other hand, via a hydrocarbonaceous group, the star corresponds to the presence of at least one asymmetric carbon in said hydrocarbonaceous group, and R represents a hydrogen atom or an alkyl radical; optionally, the radical represented by R corresponds to a hydrocarbonaceous ring linked to the hydrocarbonaceous group connecting the nitrogen and oxygen atoms.
The most widely used hydrocarbonaceous radicals are alkyl, aryl or aralkyl radicals.
The term xe2x80x9calkyl radicalxe2x80x9d is understood to mean a saturated, linear, branched or cyclic, hydrocarbonaceous group comprising from 1 to 8 carbon atoms. Mention may in particular be made, as alkyl radicals, of the methyl, ethyl, 2-propyl, 1-butyl, neopentyl (2,2-dimethyl-1-propyl), 1-hexyl, cyclohexyl, cyclopentylmethyl or tert-octyl (1,1,3,3-tetramethyl-1-butyl) radicals.
The term xe2x80x9carylxe2x80x9d is understood in particular to mean the phenyl or xcex2-naphthyl radical, optionally substituted by at least one substituent selected from an alkyl or alkyloxy radical and a halogen atom.
The term xe2x80x9caralkylxe2x80x9d is understood to mean, according to the invention, in particular xcexa9-arylalkyl, where the aryl radical and the alkyl radical are as defined above.
The hydrocarbonaceous group connecting the nitrogen and oxygen atoms is preferably a C2 alkyl radical substituted by at least one alkyl or aryl radical.
Oxaza groups are described in particular in the abovementioned publications. They are also disclosed in patents U.S. Pat. No. 4,943,635, U.S. Pat. No. 6,005,133, U.S. Pat. No. 6,037,505 and U.S. Pat. No. 6,025,531.
Preferably, the oxaza group is selected from the groups of following formulae: 
where Ph represents the phenyl radical and tBu represents the tert-butyl radical.
Advantageously, the oxaza group is selected from the groups of formulae (IV), (V), (VI) and (VII).
The compound of oxazaborolidine type according to the invention exhibits ferromagnetic characteristics which allow it to be easily separated from the reaction medium when it is used in particular as catalyst in a reaction for the reduction of prochiral ketone.
By way of comparison, the nickel nanoparticles which have reacted with boron do not exhibit ferromagnetic characteristics. Thus, no effect is observed on these particles when a magnetic field is applied.
The compound of oxazaborolidine type can also be separated from the reaction medium in which it is found by simple separation by settling.
The present invention additionally relates to a process for the preparation of the compound according to the invention which comprises the following stages:
(1) the material selected from Raney nickel, Raney cobalt and Raney iron is brought into contact with BH3 in the presence of an inert solvent,
(2) the product thus obtained is brought into contact with at least one aminoalcohol.
Preferably, the material used is Raney nickel.
The temperature of stages (1) and (2) according to the invention can vary to a large extent. It is generally between 0 and 60xc2x0 C. Preferably, the temperature employed corresponds to ambient temperature (from 20 to 30xc2x0 C.).
Stages (1) and (2) are preferably carried out under an inert atmosphere, such as, in particular, nitrogen or argon.
The inert solvent of the first reaction is selected more particularly from dioxane, diethyl ether, tetrahydrofuran, hexane, heptane, octane, cyclohexane, benzene, xylene and toluene. Preferably, tetrahydrofuran or diethyl ether is used.
Stage (2) is preferably carried out in a solvent, such as in particular one of those specified above.
More specifically, the aminoalcohol used has the general formula (VIII) 
in which the hydrocarbonaceous group connecting the nitrogen and oxygen atoms and R are as defined above.
Preferably, these aminoalcohols are selected from xcex2-aminoalcohols, such as xcex1,xcex1-diphenylpyrrolidine-methanol, (+)- or (xe2x88x92)-norephedrine, 2-amino-3-methyl-1-butanol (S or R), (1R,2S)- or (1S,2R)-2-amino-1,2-diphenylethanol, 2-amino-1,1-diphenyl-1-propanol (S or R) and 2-amino-3,3-dimethyl-1-butanol (S or R).
Preferably, before the reaction of BH3 with the material, said material is reacted with a BH4xe2x88x92 ion, in particular in the form of lithium borohydride.
The amounts of the reactants can vary to a large extent.
Preferably, the amount of BH3 used is such that the number of nickel, cobalt or iron atoms at the surface accessible to a reactant of the compound obtained is as low as possible. This amount varies according to the specific surface of the material used. To give an order of magnitude, the xe2x80x9cBH3 molecule/surface nickel, cobalt or iron atomxe2x80x9d ratio advantageously varies between 0.5 and 5.
The present invention also relates to the use of the compound according to the invention as catalyst of a reaction for the reduction of prochiral ketone to produce chiral alcohols.
Thus, the reduction process comprises a treatment of a prochiral ketone, which has to be reduced to an optically active alcohol, with a boron-based reducing agent in the presence of a catalytically effective amount of a catalyst corresponding to the compound according to the present invention.
The term xe2x80x9ccatalytically effective amountxe2x80x9d of a compound is understood to mean a substoichiometric amount which is sufficient to facilitate the conversion of a desired reactant to one or more products.
The term xe2x80x9cenantiomeric excess (e.e.)xe2x80x9d is understood to mean the excess of one of the two enantiomers over the other, generally expressed as a percentage. Thus, an enantiomeric excess of 90% corresponds to the presence of 95% of one enantiomer and of 5% of the other in the mixture in question.
The term xe2x80x9cprochiral ketonexe2x80x9d, in particular represented by the formula RSRLCO, [lacuna] a compound exhibiting a ketone functional group in which RS and RL are not identical, so that the reduction product, a secondary alcohol, of formula RSRLCHOH exhibits a chiral center on the carbon carrying the alcohol functional group.
Thus, a final subject matter of the present invention is a process for the enantioselective reduction of at least one prochiral ketone comprising a reaction of the prochiral ketone with a boron-based reducing agent in the presence of a compound according to the invention in a catalytically effective amount.
According to an alternative form of this process, the compound according to the invention is generated in situ.
The prochiral ketone having the formula RSRLCO can be any prochiral ketone in which RS and RL are inert with respect to boron. RS and RL are, independently of one another, an organic radical, such as alkyl, aryl or aralkyl (the term xe2x80x9calkylxe2x80x9d is used here in its broadest sense, that is to say in the form of a nonaromatic hydrocarbonaceous radical, and consequently includes the alkenyl radical, and the term xe2x80x9carylxe2x80x9d means an aromatic hydrocarbonaceous radical and consequently includes the phenyl and naphthyl radical).
RS and RL can be taken together to form a ring with the carbon of the ketone functional group, such as, in particular, tetralone.
RS and RL can be independently substituted by any substituent which is inert with respect to boron, such as alkyl, alkoxy, halogen, and the like.
Of course, the enantioselective nature of the reduction process of the present invention depends to a certain extent on the relative sizes of RS and RL.
The prochiral ketones more particularly used in the process according to the invention includes dialkyl ketones, such as t-butyl methyl ketone, 4-methyl-2-pentanone and methyl cyclohexyl ketone, alkyl aryl ketones, such as acetophenone, which is optionally substituted, para-methylacetophenone, para-fluoroacetophenone, propiophenone, chloroacetophenone and 2-acetyl-6-methoxynaphthalene, cyclic ketones, such as xcex1-tetralone and 2-bromo-2-cyclohexen-1-one, and the like. Prochiral ketones which are already in the chiral form, for example prostaglandin intermediates, may also be suitable.
The alcohols which are produced according to the process of the invention can be used as chiral reactants, such as 1-phenylethanol, or as intermediate in a subsequent chemical synthesis, such as optically active 1-(6-methoxy-2-naphthyl)ethanol, a synthetic intermediate for naproxen.
The boron-based reducing agents are generally selected from dimethyl sulfide-borane, tetrahydrofuran-borane (THF.BH3), N,N-diethylaniline-borane (DENA.BH3) and 1,4-thioxane-borane complexes. DENA.BH3 is preferred.
The reduction process according to the invention is carried out in an appropriate solvent, a solvent capable of diluting the ketone but which is inert to boron. Such solvents can in particular be nonbasic aprotic solvents, such as ethers (tetrahydrofuran, tetrahydropyran or diethyl ether) and aromatic hydrocarbons, such as benzene or toluene. The preferred solvents are ethers and more particularly tetrahydrofuran.